Prehabilitation and Nutritional Support to Improve Perioperative Outcomes

Lack of physical activity is one of the major modifiable risk factors of ill-health [8] and premature death, along with poor nutrition, smoking, and alcohol [9]. We live in a sedentary society in which we habitually drive cars instead of walking or cycling, sit for long periods in front of computer monitors and televisions, and build environments in which exercise and activity are minimized. Nevertheless, there is a large body of evidence supporting the notion that physical fitness has benefits in almost every context of health and disease, advocating better outcomes for fitter people [10]. Furthermore, that physical inactivity is one of the leading public health issues we face [11, 12]. A decline in physical activity as a result of aging or critical illness results in a significant increase in perioperative risk that may be attenuated by physical exercise interventions.

The link between physical activity and cancer risk is quite clear. The largest review [13•] was a pooled analysis of 12 prospective European and US cohorts that included 1.44 million participants and 186,932 cases of cancer with self-reported physical activity. This pooled analysis concluded that high levels of physical activity during leisure time (the 90th percentile compared with the 10th percentile) were associated with reduced risks of 13 types of cancer. A review [14] of 126 studies found a 10% reduction in risk across cancer types associated with physical activity, but a threshold effect meant that physical activity exceeding two times the current recommendations did not provide additional benefits. Increasing patient physical activity is therefore believed to reduce the risk of developing cancers because of its role in helping to maintain a healthy weight, although activity has numerous other beneficial effects on health and disease risk. The biological bases underlying the associations between physical activity and cancer risk are incompletely defined [15•].

Interventions to improve post-surgical recovery have usually been targeted at the intra-operative and postoperative periods. For high-risk patients about to undergo major surgery however, this is likely to be too late. Poor objectively measured physical fitness is linked to poor postoperative outcomes [16••]; therefore, identifying interventions to optimize preoperative fitness prior to major surgery is a priority. As discussed, the preoperative period may also be an emotionally salient time to engage patients in enhancing their physical fitness prior to embarking on their surgical journey. Prehabilitation is defined as “the process of enhancing the functional capacity/ physical fitness of an individual to enable them to withstand a stressful event” [1]. Physical exercise training prior to elective surgery meets this criterion.

Aerobic and muscular strength training in major surgical patients has been shown to increase endurance, improve objective markers of physical fitness, reduce weight gain, and improve muscle strength. Although constraints to proceeding with surgery limit the time for the initiation of prehabilitation, a 3-week period may still be sufficient to obtain a moderate gain in aerobic and muscle strength reserve. Importantly, in neoadjuvant cancer therapies, which are typically administered prior to surgery and followed by a recovery period of 6 to 12 weeks (or more), have opened up a time window to train patients prior to major cancer operations where previously the pressure of reducing the time between diagnosis and surgery precluded such an intervention. A critical aspect of improving physiological reserve lies in the ability to cope with surgical trauma/stress. Although a decrease in functional capacity in the period after surgery is recognized, primarily caused by surgical trauma, inflammation, or the cancer itself [1], this is further amplified by a reduced innate patient reserve. Bed rest, the need to “take it easy,” and inactivity due to cancer treatments all compound the poor outcomes we observe postoperatively.

Early studies on prehabilitation before major thoracic and abdominal surgery have shown an increase in preoperative physical fitness, physical activity, and shorter hospital stay [17‐20]. Feasibility and safety, even after neoadjuvant cancer treatments, as well as improvements in physical activity and quality of life [20, 21], have also been demonstrated. Reviews on pre-surgical exercise training in patients undergoing cancer treatments in both adjuvant and neoadjuvant periods also show a reassuring improvement in fitness, however again fall short on clearly identifying a postoperative outcome benefit [22•, 23•, 24•]. In the surgical oncology setting (adjuvant), only one study in breast cancer patients showed significant improvements in physical fitness after a 16-week exercise training program. Yet other exercise training studies showed improvements in other important outcomes such as quality of life and fatigue. In people with newly diagnosed cancer (neoadjuvant setting), three pilot studies showed clinical and significant improvements in objectively measured fitness variables after a supervised in-hospital interval training in people with rectal cancer [19] and breast cancer [25]. More recently, interest has shifted toward designing high-intensity training (HIT) programs in the preoperative setting, which may allow for effective and time-efficient exercise training before surgery [26]. Supervised HIT programs, carefully designed and individually tailored, targeting the upper and the lower body, may be a valuable addition to the perioperative pathway. However, to date, no published study has investigated HIT in people with cancer.

More recently, several systematic reviews [27, 28, 29••] have reviewed exercise prehabilitation in abdominal cancer surgery especially in colorectal surgery. They all agree that exercise prehabilitation is a possible means of enhancing physical fitness and quality of life; however, no clear impact on postoperative outcomes is currently acknowledged. Moran and colleagues [29••] reviewed studies conducting prehabilitation which consisted of inspiratory muscle training, aerobic, and resistance exercise training. These training modalities appear to decrease the incidence of postoperative complications in patients undergoing intra-abdominal surgery. However, this effect was strongest when prehabilitation was compared with usual care or breathing exercises only (OR 0.35, 95% CI 0.17–0.71). Furthermore, prehabilitation significantly decreased the incidence of postoperative pulmonary complications (OR 0.27, 95% CI 0.13–0.57), which were measured as the primary complication of interest in the majority of studies reviewed. The potential for interventions that achieve maximum results over short periods needs to be urgently explored. A recent meta-analysis concluded that interval training was more effective than continuous training at increasing fitness and demonstrated a similar safety profile for moderate-intensity training [30]. A preoperative, supervised, high-intensity program of interval training may increase a patient’s aerobic capacity prior to an operation within a short time frame [26]; however, an easier alternative is a walking-based intervention, which can be performed by patients at home. However, this type of moderate-intensity exercise may not create the improvements necessary within a short time frame. The ability of these programs to improve aerobic fitness should be compared in future research.

Encouragingly, this area of research is filled with new studies attempting to answer specific questions relating to longer term outcomes, e.g., CHALLENGE study (Colon Health and Life-Long Exercise Change) [31], the INTERVAL-MCRPC study (Intense Exercise for Survival among men with Metastatic Castrate-Resistant Prostate Cancer), and the PANTERA study (Exercise as Treatment for Men with Prostate Cancer) and started enrolment in 2016. PREPARE ABC (SupPoRtive Exercise Programmes for Accelerating REcovery after major ABdominal Cancer surgery), PREHAB (multimodal prehabilitation in colorectal cancer patients to improve functional capacity and reduce postoperative complications), and WesFIT (a pragmatic parallel group design randomized controlled study to assess the efficacy of the implementation of a prehabilitation program in patients undergoing elective major cancer surgery in Wessex, UK) trials will start recruiting later part of 2017. An improved understanding of the optimal training duration, pattern, intensity, and composition of such interventions will be needed to maximize efficacy. Furthermore, in order to maximize the effectiveness of training, a better understanding of the complex interplay between adherence, efficacy, “responders versus non-responders” to exercise, and cost for in-hospital supervised training interventions versus self-directed outpatient approaches is also urgently needed. The impact of multimodal prehabilitation and its impact on traditional surgical outcomes like morbidity, overall survival, and oncological outcomes, as well as the mechanisms driving these changes in physiology, biology, and possibly cancer biology with tailored exercise, also need exploring.

Malnutrition arises from inadequate intake and/or metabolic and inflammatory alterations that alter nutrient utilization (hypermetabolism/catabolism), requirement or absorption, which ultimately leads to wasting, cachexia, decreased physical fitness, and reduced metabolic reserve. The primary goals of nutritional prehabilitation are to optimize nutrient stores and metabolic reserve preoperatively and provide an adequate buffer to compensate for the catabolic response of critical illness or surgery. Nutritional prehabilitation is different from acutely replacing nutritional deficits. To be successful, nutritional intervention requires a timeline that needs to start at contemplation of surgery to ensure early patient engagement [32•] and must extend into the perioperative and postoperative periods. The shift to pre-emptive rather than reactive nutrition assessments and intervention must be emphasized. The recent European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines [33••] clearly show the prognostic influence of nutritional status on complications and mortality. Malnourished surgical patients have significantly higher postoperative morbidity, mortality, length of hospital stay, readmission rates, and increased costs associated with their inpatient episodes [9, 34, 35]. This risk of malnutrition is often most significant prior to and following major gastrointestinal (GI) and cancer surgery [9, 36, 37] which also often demonstrate the greatest risk of iatrogenic and baseline malnutrition (~ 65%) [38]. It is essential that the chronically malnourished cachectic cancer patient is identified via early preoperative assessment and that they receive adequate nutritional intervention prior to major surgery [32•, 37], even if it may mean a brief delay in operation time to optimize nutrition status first. Appropriate perioperative nutritional interventions have been shown to specifically improve perioperative outcomes in GI and cancer surgical patients [38], specifically reducing surgical site infections [9, 33••, 34, 35]. There is a long history of randomized controlled trials (RCTs) and meta-analyses demonstrating that preoperative nutrition (regardless of route of administration) in malnourished patients prior to GI surgery reduces postoperative morbidity by 20% [39]. Unfortunately, the success of surgery does not depend exclusively on technical surgical skills, but also on how patients respond to surgical and physiological stressors; hence, delivering nutrition, ideally preoperatively and not reactively in the perioperative period, is of utmost importance. The major effect of surgery and critical illness to induce protein catabolism also needs to be understood and emphasized. Provisions of protein, independent of whether energy or total calorie requirements, are met, can maintain lean muscle mass, and reduce the risk of subsequent frailty in the elderly [40, 41]. Finally, a recent trial conducted in colorectal surgery patients within an enhanced recover pathway demonstrated that patients receiving high protein oral nutrition supplements postoperatively (consumption of > 60% of protein needs over first 3 postoperative days) was associated with a 4.4-day reduction in length of stay (p < 0.001) [42••].

Cancer cachexia is prevalent in 50–80% of the people with cancer [43]. Cancer cachexia due to tumor-induced anorexia, catabolic effects of the tumor, abnormal metabolism of nutrients, physical obstruction of the gastrointestinal tract, reduced food intake after cancer treatment, and diminished intake due to pain, anxiety, and depression must be recognized, assessed, and intervened upon preoperatively. Traditionally, body weight and body mass index (BMI) have been used as surrogate measures of nutritional status, with large studies in patients with lung, GI, and other cancers illustrating a strong relationship between weight loss or low muscle mass and survival, i.e., people with cancer who lost more weight had reduced survival compared with those who did not lose as much weight [44]. Specifically, patients with significant weight loss and sarcopenia due to their cancer survived an average of 8 versus 28 months in patients without weight loss/sarcopenia. Body weight and BMI still remain important components of nutritional assessment, with more recent studies validating a BMI-adjusted weight loss grading system [45]. The Subjective Global Assessment (SGA) and the Patient-Generated Subjective Global Assessment (PG-SGA) screening tools are the most documented tools in the oncology literature [46•]. Numerous other screening tools have been validated for use on hospitalized patients, including the Malnutrition Universal Screening Tool (MUST), the Malnutrition Screening Tool (MST), Nutrition Risk Screening 2002 (NRS-2002), and the Short Nutrition Assessment Questionnaire (SNAQ©). A total of 32 nutritional risk assessment tools exist, which were identified in 83 studies after a systematic review of the literature [47••]. Although many nutrition screening tools do exist, there is no consensus related to the optimal screening tool for use in the preoperative “at risk” surgical patient population as all the above screening tools are intended for hospitalized patients.

Unfortunately, recent evidence reveals significant deficiencies in nutritional screening and intervention in US and European colorectal and oncologic surgical patients with only ~ 1 in five US hospitals currently utilizing a formal nutrition screening process [48•]. This is surprising as 83% of US surgeons believe existing data supports preoperative nutrition optimization to reduce perioperative complications. However, only 20% of US GI/oncologic surgery patients receive any nutritional supplements in the preoperative or postoperative setting. Overall, US surgeons recognized both importance of proper perioperative surgical nutritional support and the potential value to patient outcomes.

A combination of both individualized nutrition counseling, oral nutritional supplements, and exercise has been proven to be effective in building physical fitness in prehabilitation trials [66, 67•, 68‐70]. In 2013, Denison and colleagues [71•] conducted a systematic review including 17 randomized controlled trials (RCTs) to explore the effect of combined exercise and nutrition intervention to improve muscle mass, muscle strength (measures of sarcopenia), and physical performance in older people (all over 60 years old). They concluded that further studies were needed to provide evidence upon which public health and clinical recommendations could be based. A recently updated systematic review from the same group [72••] was published identifying 21 additional RCTs (total of 37 RCTs). In 79% of the studies (27/34 RCTs), muscle mass increased with exercise but an additional effect of nutrition was only found in eight RCTs (23.5%). Muscle strength increased in 82.8% of the studies (29/35 RCTs) following exercise intervention, and dietary supplementation showed additional benefits in only a small number of studies (8/35 RCTS, 22.8%). The majority of studies showed an increase of physical performance following exercise intervention (26/28 RCTs, 92.8%), but interaction with nutrition supplementation was only found in 14.3% of these studies (4/28 RCTs). The review concludes that physical exercise has a positive impact on muscle mass and muscle function in healthy subjects aged 60 years and older with a large effect seen with exercise interventions of any type. However, a large variation in regard to the dietary interventions was found, and this is likely to be essential to potential benefit, especially with regard to protein content, type, supplemental nutrient delivery, and overall total caloric delivery. Moreover, using the selected inclusion criteria, the studies, this review captured, predominantly included well-nourished elderly subjects; hence, its translatability to a malnourished surgical population is very limited.

Very few well-designed multimodal exercise and nutrition prehabilitation studies have been undertaken. Gillis and colleagues [68] undertook a parallel-arm single-blind superiority randomized controlled of 70 colorectal cancer patients who were randomized to receive either prehabilitation (n = 38) or rehabilitation (n = 39). The prehabilitation group increased their functional walking capacity by ≥ 20 m compared with the rehabilitation alone group (53 vs. 15%, adjusted p = 0.006). Complication rates and duration of hospital stay between the two groups were similar. Another study published by the same group [67•] undertook a study to interrogate the impact of nutrition counseling and whey protein supplementation on preoperative functional walking capacity and recovery in patients undergoing colorectal resection for cancer. A double-blinded randomized controlled trial in 48 patients scheduled for elective colon cancer surgery was randomized to receive either individualized nutrition counseling with whey protein supplementation to meet protein needs or individualized nutrition counseling with a nonnutritive placebo. Counseling and supplementation began 4 weeks before surgery and continued for 4 weeks after surgery. Clinically meaningful improvements in functional walking capacity were achieved before surgery with whey protein supplementation. Burden [69] evaluated the effect of preoperative standardized oral supplements in a cohort of colorectal cancer patients. In a randomized controlled trial, patients were assigned to receive 400 mL of oral supplement and dietary advice or dietary advice alone. The intention-to-treat analysis identified no statistically significant difference between the intervention and control groups for the primary outcome (i.e., total postoperative complications). The results of the ongoing multimodal prehabilitation exercise and nutrition studies, with clinically relevant endpoints, will be reported in the next few years and inform our management.

Substantial gains to improve surgical outcomes via optimization, utilizing multimodal prehabilitation intervention, are yet to be made. We know that poor preoperative physical fitness reflecting poor physiological reserves is associated with postoperative morbidity, and that prehabilitation prior to acute or chronic stressors can improve fitness and quality of life. A number of promising opportunities are being developed in perioperative medicine, including increasingly sophisticated risk prediction, collaborative decision-making, personalized medicine, and targeted multimodal interventions. It therefore seems reasonable to enhance our current preoperative assessments by incorporating nutritional and objective preoperative physical fitness risk screening that is intuitively easy to comprehend. The idea of “fitness for surgery” is essential for discussions about the specific risks and benefits of a particular procedure for a particular patient. Personalized medicine, via prescribing tailored exercise and nutritional interventions, aimed at improving surgical outcomes may be used to guide operative interventions, postoperative care, cancer therapies (including the selection of chemotherapy and timing of cancer treatments in relation to surgery), and choices of appropriate multimodal prehabilitation/rehabilitation programs. Mechanisms underpinning the interactions of changes in fitness with changes in tumor microenvironment, cancer therapies, and exercise are largely unknown, so work within this area is urgently needed.